Although 18 genetic variants have now been identified as conferring resistance to severe malaria, mostly in west Africans, only a subset have been replicated in multiple studies. Here we propose to assess genetic susceptibility to malaria in the Luo, an East African population from an ethnic background very different from the populations in which most of the associations were previously identified. We hypothesize that identifying genetic variation affecting susceptibility to malaria will lead to new drug targets, but that several of the candidate variants so far may not be real and thus need to be replicated. We also propose to search for new susceptibility variants, via the first whole-genome scan for malaria resistance genes. The first phase of this project will be to carry out a replication study for malaria susceptibility. We will study the 18 genetic variants previously associated to malaria resistance in 539 Luo cases and 477 matched controls. For the nine genes in which these variants occur, we will also create "haplotype maps" specific for the Luo population, and identify all the haplotypes of >5 percent frequency and assess whether any of them are associated to malaria resistance. The haplotype analysis in these genes is significant because it will allow us to identify new risk variants present only in East Africa, where few studies have been done. The second phase will be to search for a history of natural selection at nine genes associated with malaria resistance. We recently published a protocol to search for regions of the genome that have been affected by natural selection. We used this to establish evidence for selection at CD40 ligand and G6PD (two genes previously associated with malaria resistance). We now propose to use the same protocol to search for evidence of natural selection at all nine genes associated with malaria resistance in east Africans. As a second test for selection, we will also compare the frequencies of the malaria resistance haplotypes in the Luo to those in the Masai, a population that is also of Nilotic in origin like the Luo, but has historically lived in a low-malaria environment. The finding of a haplotype that is very different in frequency comparing the Luo and Masai, despite the similar ethnic background, would suggest the presence of a malaria resistance gene. The third phase will be to carry out a pilot whole-genome scan for malaria resistance genes. All the genes that were previously associated to resistance fo malaria were identified by the "candidate gene" approach, where a handful of genes that were specifically believed to be significant for malaria pathogenesis, were tested for association. However, it may be that some of the most interesting drug targets are in the mass of genes that have not yet been tested. We propose to carry out the first whole-genome association scan to find malaria resistance genes, using Affymetrix gene-chip technology to scan a panel of 50,000 variants in up to 200 Luo severe malaria cases, 200 healthy Luo controls, and 100 healthy Masai. We will search not only for differences in frequencies between Luo cases and controls, but also for regions that are strikingly different in frequency between the Luo and Masai despite their similar ethnic origin, suggesting selection for malaria resistance in Luo in the past few thousand years. [unreadable] [unreadable] [unreadable]